Osteoarthritis (OA) is a common joint disease, characterized by joint pain and stiffness; and cartilage damage is the main cause of osteoarthritis. Osteoarthritis occurs more frequently in people after middle age, and more frequently in female than in male. The prevalence of osteoarthritis is 10%-17% in 40-year-olds, 50% in people aged 60 and above, and as high as 80% in people aged 75 and above. Osteoarthritis has a certain disability rate. With the aging of the population, osteoarthritis will become an important issue affecting quality of people's life, and the market demand for osteoarthritis drugs will continue to expand.
Currently, the therapeutic drugs for osteoarthritis in clinical practice are classified into specific therapeutic drugs and non-specific therapeutic drugs. The non-specific therapeutic drugs, such as non-steroidal anti-inflammatory drugs, are mainly used for analgesia and symptom control, but have no protective effect on cartilage. The specific therapeutic drugs, such as glucosamine, chondroitin sulfate, diphosphonate, etc., can protect articular cartilage and delay the progression of osteoarthritis. However, the specific therapeutic drugs generally have a relatively slow-acting effect, requiring several weeks of treatment. Moreover, the specific therapeutic drugs have no effect on the regeneration of damaged cartilage. Therefore, developing a novel osteoarthritis drugs with good safety and outstanding efficacy has become a major goal in the medical field.
Cartilage damage is a main cause of osteoarthritis. Articular cartilage is composed of abundant extracellular matrix (ECM) and a limited number of chondrocytes embedded in the EMC. The metabolism of chondrocytes is regulated by many cytokines, among which, bone morphogenetic protein (BMP) plays an important role in the synthesis and metabolism of bone and cartilage.
Bone morphogenetic protein, also known as bone formation protein, is an acidic polypeptide capable of inducing bone formation and chondrogenesis at an ectopic site outside of bone. BMP is a hydrophobic acid glycoprotein with a molecular weight of 18000 D and is composed of more than ten kinds of amino acids. BMP has stable performance under acidic conditions and has a certain solubility in a solution with a pH of 7.2. When the pH of the solution is greater than 8.5, BMP is completely inactivated.
BMPs are a group of multifunctional growth factors belonging to the TGF-β superfamily, and more than 20 family members have been identified and described. A large number of literatures indicate that BMP can induce mesenchymal cells to proliferate and differentiate into osteoblasts or chondrocytes. BMP plays a key role in the occurrence, induction and repair of bone, and can affect growth, differentiation and apoptosis of cells. BMP can significantly promote the growth and maturation of cultured chondrocytes, and plays a key role in the occurrence and development of various tissues.
BMP-2 is an acidic polypeptide, and has a strongest ability of inducing bone marrow mesenchymal stem cells to differentiate into osteoblasts among the BMP superfamily. However, the half-life of the BMP-2 is relatively short, the therapeutic concentration of BMP-2 is difficult to maintain, and BMP-2 cannot act on more target cells in an effective time, so the induction activity of BMP-2 cannot be fully exerted, and the clinical application of BMP-2 has been greatly limited. Currently, recombinant BMP-2 is the most commonly studied BMP-2 drugs. As mentioned above, BMP-2 has poor stability and short half-life, so there is an urgent need to develop a novel drug to overcome the defects of recombinant BMP-2.